Fawaz Maria V, Brooks Allen F, Rodnick Melissa E, Carpenter Garrett M, Shao Xia, Desmond Timothy J, Sherman Phillip, Quesada Carole A, Hockley Brian G, Kilbourn Michael R, Albin Roger L, Frey Kirk A, Scott Peter J H
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
ACS Chem Neurosci. 2014 Aug 20;5(8):718-30. doi: 10.1021/cn500103u. Epub 2014 Jun 16.
Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.
异常聚集的tau蛋白是tau蛋白病神经退行性疾病的标志性病理特征，也是整个tau蛋白病疾病谱中诊断工具和治疗策略开发的靶点。开发对tau蛋白具有适当亲和力和特异性的碳-11或氟-18标记的放射性示踪剂，将允许使用正电子发射断层扫描（PET）成像对tau蛋白负担进行无创定量。我们已经合成了[(18)F]兰索拉唑、[(11)C]N-甲基兰索拉唑和[(18)F]N-甲基兰索拉唑，并将它们鉴定为对tau蛋白具有高亲和力的放射性示踪剂，其结合亲和力低至亚纳摩尔。在此，我们报告了放射性合成和广泛的临床前评估，目的是选择一种先导放射性示踪剂用于转化为人体PET成像试验。我们证明，[(18)F]N-甲基兰索拉唑由于氟-18的半衰期适宜、在非人灵长类动物中快速进入大脑、动力学良好、白质结合低以及对tau蛋白的结合选择性高于淀粉样蛋白，是推进临床试验的先导化合物。
